Glucokinase (sometimes to be abbreviated as GK in the present specification) (EC2.7.1.1) is one of the four kinds of hexokinases found in mammals, and is also called hexokinase IV. GK is an enzyme that catalyzes conversion of glucose to glucose-6-phosphoric acid, which is the first step of the glycolytic pathway. GK is mainly present in pancreatic β cells and the liver, and acts as a sensor of extracellular glucose concentration that defines glucose-stimulated insulin secretion in pancreatic β cells. In the liver, the enzyme reaction of GK is a rate-limiting factor to regulate glycogen synthesis and glycolysis. Three hexokinases (I, II, III) other than GK show the maximum enzyme activity at a glucose concentration of not more than 1 mM. In contrast, GK shows low affinity for glucose, and the Km value thereof is 8-15 mM, which is close to the physiological blood glucose level. Accordingly, promotion of intracellular glucose metabolism via GK occurs in response to the changes in the blood glucose level from the normal blood glucose (5 mM) to the postprandial hyper-blood glucose (10-15 mM).
The hypothesis proposed by Matschinsky et al. in 1984 that GK functions as a glucose sensor in pancreatic β cells and hepatocytes has been demonstrated through analysis of glucokinase gene engineered mouse in recent years (see The Journal of Biological Chemistry, 1995, vol. 270, pages 30253-30256; The Journal of Biological Chemistry, 1997, vol. 272, pages 22564-22569; The Journal of Biological Chemistry, 1997, vol. 272, pages 22570-22575; Japan clinical, 2002, vol. 60, pages 523-534; and Cell, 1995, vol. 83, pages 69-78.)
To be specific, GK heterozygous deleted mouse showed hyperglycemia and impaired glucose-stimulated insulin secretion. GK homozygous deleted mice die of marked hyperglycemia and sugar urine some time soon after birth. On the other hand, in GK overexpressing mice (hetero type), lower blood glucose level, higher blood glucose clearance rate, increased liver glycogen content and the like were observed. From these findings, it has been clarified that GK plays an important role in systemic glucose homeostasis. In other words, lower GK activity causes insulin hyposecretion and lower liver glucose metabolism, and the onset of impaired glucose tolerance and diabetes. Conversely, enhanced GK activity due to the activation or overexpression of GK causes enhanced insulin secretion and promoted liver glucose metabolism, which in turn increases systemic glucose utilization and improves glucose tolerance.
In human, too, it has been clarified from the analysis of GK gene abnormality reported mainly in the families of juvenile-onset adult diabetes called MODY2 (Maturity Onset Diabetes of the Young) that GK acts as a glucose sensor and plays an important role in glucose homostasis (see Nature, 1992, vol. 356, pages 721-722).
In GK gene abnormality, blood glucose threshold value of insulin secretion increases and insulin secretion ability decreases due to the decreased affinity of GK for glucose (increased Km value) and decreased Vmax. In the liver, decreased glucose uptake, promotion of gluconeogenesis, lower glycogen synthesis and liver insulin resistance are observed due to the decreased GK activity. On the other hand, some families having a mutation that increases the GK activity have been found, and in such families, fasting hypoglycemia accompanying increased plasma insulin concentration is observed (see New England Journal Medicine, 1998, vol. 338, pages 226-230).
As mentioned above, GK functions as a glucose sensor in mammals including human, and plays an important role in blood glucose control. Incidentally, blood glucose control utilizing the glucose sensor system of GK in many type 2 diabetic patients is considered to open a new way to a diabetes treatment. Particularly, a GK activating substance is considered to be useful as a drug for the prophylaxis or treatment of type 2 diabetes, since an insulin secretagogue action in pancreatic β cells, and glucose uptake promotion and glucose release inhibitory action in the liver can be expected.
Recently, pancreatic β cell type glucokinase has been clarified to be regionally expressed in the feeding center (Ventromedial Hypothalamus: VMH) of the rat brain. A subset of nerve cells present in VMH is called glucose responsive neuron and plays a key role in the body weight control. According to electrophysiological experiments, this neuron is activated in response to physiological changes in the glucose concentration (5-20 mM). Since the VHM glucose concentration sensor system assumes a mechanism mediated by glucokinase, as in the case of insulin secretion by pancreatic β cells, a pharmaceutical agent capable of glucokinase activation in the VHM besides the pancreatic β cells and liver is potentially capable of achieving not only a blood glucose correction effect but also improvement of obesity.
As mentioned above, a pharmaceutical agent capable of GK activation is useful as a drug for the prophylaxis or treatment of diabetes and chronic diabetic complications such as retinopathy, nephropathy, neurosis, ischemic cardiac diseases, arteriosclerosis and the like, and further as a drug for the prophylaxis or treatment of obesity.
As imidazopyridine compounds, it has been reported that a compound represented by formula:

wherein
X, X1-X4 are each C or N;
ring A is a 5- or 6-membered nitrogen-containing aromatic heterocycle which is optionally condensed with phenyl or pyridyl;
R1 is an optionally substituted aryl or an optionally substituted 4-10-membered heterocycle;
X5 is —O—, —S—, —SO—, —SO2—, a single bond or —O—C1-6 alkylene-;
q and m are each 0-2;
R2 is a hydroxy group, a formyl group and the like; and
R3 is a C1-6 alkyl group and the like is a glucokinase activator, which is useful for the treatment of diabetes, complications, obesity and the like (see WO2005/063738).
However, the above-mentioned literatures do not disclose that compounds represented by the following formula (I) have a glucokinase activating action, nor do they disclose a compound represented by the following formula (II).